Use of sustained release dexamethasone in post-cataract surgery inflammation

ABSTRACT

The present embodiments provide for a treatment regimen and use of a short-term sustained release liquid formulation of dexamethasone in citrate, wherein a single administration of a minute dosage form into the anterior chamber of the eye provides for anti-inflammatory therapy following cataract surgery.

RELATED APPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 14/893,381, filed Nov. 23, 2015, national phase of PCT/US14/39319,filed May 23, 2014, which claims priority benefit of Provisional Appl.No. 61/827,091, filed May 24, 2013, each of which is incorporated fullyherein by reference.

BACKGROUND

A cataract is clouding of the lens of the eye, which impedes the passageof light. Most cataracts are related to ageing, but occasionallychildren are born with the condition; or the cataract may develop afteran injury, inflammation, or disease. Risk factors for age-relatedcataracts include diabetes, prolonged exposure to sunlight, tobacco use,and excessive alcohol consumption.

Vision can be restored by surgically removing the affected lens, and inmost cases replacing it by an artificial one. Indeed, in Westerncountries the rate of cataract surgery has increased significantlyduring the past two decades. In many countries, cataract surgery nowaccounts for over half of all ophthalmic surgery and has become the mostcommon elective surgical procedure. Although today the removal of theopaque lens and its replacement with an artificial one represents aroutine operation that involves only minor risks, it consumes aconsiderable share of the resources for ophthalmic care. Minimizing theside effects of cataracts procedures and impact of the health caresystem remains an important goal.

In addition to antibiotic eye drops to prevent infection,anti-inflammatory eye drops are also prescribed to help reduce anyinternal inflammation. These eye drops are in some cases started beforesurgery, and in some cases must be continued for 2 or 3 months.Compliance with dosing and application regimens in order to minimize theside effects of inflammation can be challenging for many patients. Thequicker any inflammation is resolved the quicker the patient realizesthe full desired therapeutic outcome of the surgery and can resumenormal daily activities. Additionally, the use of eye drops to deliverymedication into the eye is at best marginally effective. In most casesonly a small percentage of the dose actually enters the eye. This factoralong with compliance issues limit the effective drug levels that can beachieved using eye drop technology. Therefore, there is a need forsustained release anti-inflammation therapy that can benefit thecataract patient by replacing the need for anti-inflammatory eye drops.In particular, there is a need for a formulation and method thatdelivers highly effective drug levels without the issues associated witheye drops, which formulation results in superior clinical results.

SUMMARY

The present embodiments provide for the post-cataract surgery use of aneasily injectable, short-term sustained release formulation forsustained release of the anti-inflammatory drug dexamethasone for aboutone to three weeks. In one embodiment, the formulation consistsessentially of dexamethasone in a citrate vehicle, in which one dosevolume ranging from about 1 μL to about 12 μL of a formulationconsisting essentially of dexamethasone at a concentration ranging fromabout 1% to about 20% (w/w) in about 80% to about 99% citric acid esteror a citric acid ether, is injected into the anterior chamber of the eyefor treating inflammation after cataract surgery. In particular exampleembodiments, a patient having undergone cataract surgery is administeredabout 5 μL of a formulation consisting of about 6%, about 9% or about12% (w/w) dexamethasone in triethyl acetyl citrate, which is injectedinto the anterior chamber of the eye. In use, inflammation is controlledpost-cataract surgery by this single, minute volume injection. Thepresent medication regimen replaces steroidal eye drops and providesimproved benefit in ease of treatment, patient compliance, and clinicaloutcome for cataract surgery patients.

An aspect of the present embodiments provides for use of a formulationconsisting of about 1 μL to about 12 μL of a composition consistingessentially of about 1% to about 20% (w/w) dexamethasone and about 80%to about 99% (w/w) triethyl acetyl citrate, that is administered as asingle dose by injection into the anterior chamber of eye for thetreatment of inflammation following cataract surgery, wherein saiddosage form releases dexamethasone for at least 3 days as measured insaline solution under infinite sink conditions. In particularembodiments, the formulation of said use includes about 6% (w/w)dexamethasone; about about 9% (w/w) dexamethasone; or about 12% (w/w)dexamethasone. In another embodiment, the use of the formulation resultsin an anterior chamber cell count below 2 within 30 days ofadministration when assessed by slit lamp microscopy. In yet anotherembodiment, the use of the formulation comprises an injection deliveredusing a needle; or an injection delivered using a cannula.

Another aspect of the embodiments provides for a unit dosage consistingessentially of about 1% to about 20% (w/w) dexamethasone and about 80%to 99% triethyl acetyl citrate, wherein said dosage form releasesdexamethasone for at least 3 days, as measured in saline solution underinfinite sink conditions. In some embodiments, the unit dosage formcomprises about 200 μg to about 800 μg of dexamethasone; about 342 μg ofdexamethasone; about 517 μg of dexamethasone; or about 697 μg ofdexamethasone. In other embodiments, the total volume of said unitdosage form is about 1 μL to about 12 μL; about 4 μL to about 6 μL; orabout 5 μL. In other embodiments, the unit dosage form releasesdexamethasone for at least 7 days, as measured in saline solution underinfinite sink conditions. In particular embodiments, the unit dosageform releases said dexamethasone for at least 7 days, but no more than35 days, as measured in saline solution under infinite sink conditions.In other embodiments, the unit dosage form retains at least 30% of itsdexamethasone after 3 days, as measured in saline solution underinfinite sink conditions.

Another embodiment provides for a unit dosage for the treatment ofinflammation following cataract surgery consisting of a unit dose ofabout 5 μL of a formulation consisting essentially of either 342 μg, 517μg or 697 μg dexamethasone in triethyl acetyl citrate, wherein the unitdose is injected into the anterior chamber of the eye following cataractsurgery, and wherein administration results in an anterior chamber cellcount below 2 within 30 days of administration when assessed by slitlamp microscopy.

Another aspect of the present embodiments provides for a kit comprisinga pre-filled syringe or pre-filled vial containing a formulationconsisting essentially of dexamethasone and triethyl acetyl citrate in aw/w dexamethasone:triethyl acetyl citrate ratio of about 6:94, about9:91, or about 12:88; and injection syringe, a 25 gauge cannula or 28gauge needle or 30 gauge needle that is, optionally, connected to thesyringe; a dose loading guide; optionally, a dose delivery guide; andinstructions for administration; wherein a single unit dose of about 5μL of the formulation of the kit is injected into the anterior chamberof the eye for treating inflammation following cataract surgery.

Still another aspect of the embodiments provides for a method oftreating inflammation following cataract surgery in a patient in needthereof, comprising injecting into the anterior chamber of the eye ofthe patient about 1 μL to about 12 μL of a composition consistingessentially of about 1% to about 20% (w/w) dexamethasone and about 80%to about 99% (w/w) triethyl acetyl citrate. In some embodiments of thisaspect, the administration results in an anterior chamber cell countbelow 2 within 30 days of administration, when assessed by slit lampmicroscopy; or the administration results in an anterior chamber cellcount below 3 within 8 days of administration, when assessed by slitlamp microscopy. In other embodiments, the composition releasesdexamethasone for at least 3 days, as measured in saline solution underinfinite sink conditions. In other embodiments, the composition of themethod includes about 200 μg to about 1100 μg of dexamethasone; about342 μg of dexamethasone; about 517 μg dexamethasone; or about 697 μgdexamethasone. In still other embodiments of the method, the total dosevolume of the composition is about 4 μL to about 7.5 μL.

Another aspect of the present embodiments provides for a unit dosageform comprising a prefilled syringe comprising about 1 μL to about 12 μLof a composition consisting of 1% to 20% (w/w) dexamethasone and 80% to99% (w/w) triethyl acetyl citrate, wherein said dosage form releasessaid dexamethasone for at least 3 days but no more than 35 days asmeasured in saline solution under infinite sink conditions.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the average in vitro dexamethasone (Dex) release from 5 μLaliquots of three formulations of Dex in triethyl acetyl citrate (ΛTEC),as a percent of Dex release per day in a 10 mL saline infinite sink,n=6: ●342 μg/5 μL; ▪517 μg/5 μL; ▴697 μg/5 μL.

FIG. 2 shows the average in vitro Dex release from two formulations ofDex in ATEC, as percent release per day in a 20 mL saline infinite sink,n=6: ▴342 μg/5 μL; ▪517 μg/5 μL.

FIG. 3 shows the average in vitro Dex release from two formulations ofDex in ATEC, as percent release per day in 20 mL saline/β-cyclodextrin,n=6: ▴342 μg/5 μL; ▪517 μg/5 μL.

FIG. 4 shows the average in vitro Dex release from two formulations ofDex in ATEC as percent release per day in 20 mL saline/Tween-80, n=6:▴342 μg/5 μL; ▪517 μg/5 μL.

FIG. 5 presents data on the viscosities of three formulations of Dex inATEC. ♦342 μg/5 μL; ∘517 μg/5 μL; ▴697 μg/5 μL.

FIG. 6 shows in vivo pharmacokinetic release of dexamethasone into theaqueous humor of rabbit eyes following injection of 5 μL into theanterior chamber of one of three different formulations of dexamethasonein ΛTEC: ●342 μg/5 μL; ▴517 μg/5 μL; ▪697 μg/5 μL. The data demonstratethat dexamethasone was released for 11 to 21 days.

FIG. 7 shows the proportion of patients with ACC grade=0 at day 8following cataract surgery and administration of a single 5 μL unit doseof one of three concentrations of Dex in ATEC, as indicated.

FIG. 8 shows the secondary endpoint in a Phase II clinical trial (ofcataract surgery patients treated with a single administration of theformulations as in FIG. 7), as the proportion of patients with ACCGrade=0 over time. ♦342 μg/5 μL; ▪517 μg/5 μL; ▴697 μg/5 μL. Verticalbats are ±1 standard error of the unadjusted mean. Thelast-observation-carried-forward (LOCF) method was used to imputemissing data.

FIG. 9 is a graph showing the percent of patients exhibiting anteriorchamber cell clearing in twenty-six human cataract surgery patientsinjected with dexamethasone in citrate, as described herein, comparedwith published data on anterior chamber cell clearing using twocommercially available products: dexamethasone from Surodex® implantsand difluprednate from Durezol® eye drops. Dots: dexamethasone incitrate; hatching: Surodex® implants; cross-hatching: Durezol®difluprednate eye drops.

DETAILED DESCRIPTION

It should be understood that this invention is not limited to theparticular methodology, protocols, and reagents, etc., described hereinand as such may vary. The terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to limit thescope of the present invention, which is defined solely by the claimsUnless defined otherwise, all technical and scientific terms used hereinhave the same meaning as those commonly understood to one of ordinaryskill in the art to which this invention pertains.

As used herein and in the claims, the singular forms “a,” “an,” and“the” include the plural reference unless the context clearly indicatesotherwise. The term “or” is inclusive unless modified, for example, by“either.” Other than in the operating examples, or where otherwiseindicated, all numbers expressing quantities of ingredients or reactionconditions used herein should be understood as modified in all instancesby the term “about.” The term “about” in relation to percentages,generally means±1%. “Consisting essentially of” means that theformulations described herein can contain additional ingredients that donot interfere with effectiveness of the drug product or drug release;or, in general, the formulations may contain additional ingredients thattotal less than 1%, 0.5% or 0.1% of the formulation, or are present intrace amounts.

All patents and other publications identified are incorporated herein byreference for the purpose of describing and disclosing, for example, themethodologies described in such publications that might be used inconnection with the present invention, but are not to providedefinitions of terms inconsistent with those presented herein. Thesepublications are provided solely for their disclosure prior to thefiling date of the present application. Nothing in this regard should beconstrued as an admission that the inventors are not entitled toantedate such disclosure by virtue of prior invention or for any otherreason. All statements as to the date or representation as to thecontents of these documents is based on information available to theapplicants and do not constitute any admission as to the correctness ofthe dates or contents of these documents.

Currently cataract surgery is accompanied by a lengthy and messy regimenof eye drops that are required to reduce inflammation in the eye. Forexample, following cataract surgery, prednisolone eye drops aretypically applied four times daily for the first week, three times dailyfor the second week, two time daily for the third week, and once dailyfor the fourth week and beyond until the bottle runs dry. Additionallyand concurrently, ketorolac eye drops are applied four times daily forthe first through the fourth weeks following cataract surgery. Theseanti-inflammatory eye drops are used along with other eye drops such asantibiotic eye drops. The anti-inflammatory eye drops are sometimesopaque and render vision blurry. They are also messy, as the eye floodswith drops and insoluble components collect in the corner of the eyes oron the eye lids. Moreover, many individuals have trouble applying thesedrops formulations correctly, with the right amount of dosing at theright time, for the correct length of weeks. In other words, beyond theinconvenience of such eye drops, compliance in the eye drops dosingregimen can be an issue.

The present embodiments provide for the use of an anti-inflammatoryformulation in treating an acute inflammatory response to a surgicalevent. In particular, the present embodiments relate to the treatment ofinflammation following cataract surgery comprising, in a particularembodiment, injecting into the anterior chamber of the eye a smallvolume, for example a dose form having a volume of about 4 μL to about12 μL, of a liquid formulation consisting essentially of dexamethasonein citrate, for example triethyl acetyl citrate. Although the release issustained release, the dosage form herein provides for relativelyshort-term sustained release of the active drug, lasting from about oneto three weeks. By design, the formulation delivers a relatively highdose of dexamethasone very quickly to give a quick response; it thentapers off quickly to minimize the potential of any adverse eventsassociated with the use of steroids. This liquid formulation maintains asingle, generally spherical bolus shape (a monolithic shape or cohesivestructure), at the site of placement; is biocompatible, biodegradable;provides for the sustained release of dexamethasone; then disappearsentirely after delivering dexamethasone to the desired site. Theformulations provide for novel post-cataract surgery therapy that ismanipulated easily and injected by qualified medical practitioners, andcan be used instead of the current anti-inflammatory eye drops regimenor solid implants. This use avoids the inconvenience and complianceissues associated with the current anti-inflammatory eye drops regimen,by replacing it with a physician-administered, one-time application thatassures correct dosing, compliance, and provides beneficialanti-inflammatory therapy following cataract surgery.

Dexamethasone is an anti-inflammatory glucocorticoid. Its chemical namesinclude(11β,16α)-9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione;9α-Fluoro-16α-methylprednisolone; and16α-methyl-9α-fluoro-1,4-pregnadiene-11β,17α,21-triol-3,20-dione.Pharmaceutical formulations of dexamethasone include dexamethasone,dexamethasone acetate and dexamethasone sodium phosphate. Thus, the termdexamethasone refers to dexamethasone salts, acids, variants,polymorphs, derivatives, prodrugs and metabolites, etc., that have (orwill have) regulatory approval for use as anti-inflammatories for use inthe eye.

Citrates, as used herein, include citric acid esters or citric acidethers such as triethyl citrate (TEC), acetyl triethyl citrate (ATEC)and tributyl citrates such as acetyl tributyl citrate (ATBC) andtributyl citrate (TBC). Citrates vary in hydrophilicity orhydrophobicity, and citrates may be used in combination. Active agentscan be dissolved, dispersed, emulsified or suspended in citrates andform liquids, gels or solids depending on the citrate(s) and activeagents used in a particular formulation. In vitro and animal in vivostudies have reported the use of various citrates as sustained releasevehicles. See U.S. Pat. No. 7,906,136, U.S. Pat. No. 7,560,120, U.S.Pat. No. 6,960,346; U.S. Patent Appl. Pub. No. 2011/0111006. Aparticularly useful citrate for the short-term sustained release ofdexamethasone in the anterior chamber of the eye is acetyl triethylcitrate (also called ATEC, triethyl acetyl citrate, TEAC, triethyl0-acetyl citrate, or 1,2,3-Propanetricarboxylicacid,2-(acetyloxy)-triethyl ester).

Embodiments of the present invention use a citrate vehicle, inparticular ATEC, as the delivery vehicle for dexamethasone in thetreatment of inflammation following surgery for cataract(s). The dosevolume of the formulation administered into the eye is relativelyminute, in a range of from about 1 μL to about 12 μL, inclusive, forexample, about 3 μL to about 10 μL, about 2.5 μL, to about 7.5 μL, orabout 4 μL to about 6 μL, inclusive, such as about 5 μL, about 7.5 μL orabout 10 μL as a single dose delivered into the eye by injection.

The amount of dexamethasone in the formulation can be expressed instrength, such as from about 100 micrograms (μg) to about 1100 μg perdose, inclusive, for example about 200 μg to about 800 μg, about 300 μgto about 750 μg, about 300 μg to about 400 μg, about 500 μg to about 600μg, and about 650 μg to about 750 μg, inclusive, such as about 114 μg,about 342 μg, about 513 μg, about 517 μg, about 684 μg, about 697 μgabout 776 μg, or about 1046 μg. The amount of dexamethasone in theformulation can also be expressed as a range in concentration of fromabout 1% to about 45% dexamethasone (w/w), inclusive, for example, about2% to about 35%, about 3% to about 25%, about 3% to about 20% about 5%to about 15%, about 4% to about 14% (w/w) dexamethasone, inclusive, suchas about 1%, 4.5%, 6%, 9% or 12% (w/w) dexamethasone. The amount of in acitrate vehicle, such as ATEC, in the formulation can range from about55% to about 99% (w/w) citrate, inclusive, for example, about 65% toabout 85%, about 75% to about 97%, about 80% to about 97%, about 85% toabout 95%, about 86% to about 96%, inclusive, such as about 91%, about94%, or about 88%.

In other words, it is possible to design a dosage form in which a volumeof about 4 μL to about 12 μL consists essentially of from 1% to 45%dexamethasone in corresponding 55% to 99% citrate. Thus, in aformulation consisting essentially of dexamethasone and ATEC, the weightratio of dexamethasone:ATEC can be about 1:99, about 3:97, about 4:96,about 4.5:95.5, about 6:94, about 9:91, about 12:88, or about 20:80,inclusive. More specifically, for a low dose formulation consisting of6% dexamethasone, a 5 μL dose weighs 5.7 mg, and contains 0.342 mgdexamethasone and 5.358 mg ATEC; for a medium dose of 9% dexamethasone,a 5 μL dose weighs 5.75 mg, and contains 0.5175 mg dexamethasone and5.2325 mg ATEC. Alternative dosage forms include, for example, thefollowing amounts of dexamethasone in the given dose volume: about 342μg/about 5 μL, about 517 μg/about 5 μL, about 697 μg/about 5 μL, about1046 μg/about 7.5 μL, about 776 μg/about 7.5 μL, about 513 μg/about 7.5μL, about 513 μg/about 10 μL, about 684 μg/about 10 μL, or about 114μg/about 10 μL.

A single administration of the dosage form, for example about 5 μL,about 7.5 μL or about 10 μL, into the anterior chamber of the eye canalleviate inflammation and replace the current eye drops regimen or theneed for solid implants in patients in need thereof, i.e., followingcataract surgery.

After the cataract surgery—any type of cataract surgery, such asphacoemulsification or extracapsular cataract surgery—is completed, theformulation is administered into the anterior chamber through a smallgauge cannula or needle. The dosage form can be placed in the anteriorchamber of the eye, either in front of or behind the iris, and thedosage form does not interfere with the patient's vision. Theformulation can be administered using a cannula and vial, a prefilledvial, or prefilled syringe. A small gauge cannula and syringe can beused for administration behind the iris, but a small gauge needle canalso be used, especially for injection in front of the iris. Forexample, at 25 gauge cannula (e.g., single use, anterior chambercannula, 25 gauge, 8 mm, bend to tip from MSI Precision SpecialtyInstruments, Phoenixville, Pa.) or 28 or 30 gauge needle are suitable toadminister the dosage form, for example from about 4 μL to about 12 μL,inclusive, such as about 5 μL, about 7.5 μL or about 10 μL into theanterior chamber. Because the formulation retains its monolithic shapeafter injection, the physician can view proper placement of theformulation dosage form. After administration, as the dexamethasone isdelivered by sustained release from the dosage form, the formulationdisappears leaving behind nothing. The use of one administration ofabout 4 μL to about 12 μL of this dexamethasone formulation issufficient to provide relief from inflammation following cataractsurgery, and is may be used without the use of additionalanti-inflammatory therapy such as steroidal or non-steroidalanti-inflammatory eye drops or solid implants.

A dosing guide for a syringe can be used to accurately load and deliverthe minute volume of the present regimen. See WO 2012/149040. Briefly,an injection syringe is filled in excess of the volume required for thecorrect dose, and a spacer that is configured to regulate the doseloaded into the syringe is inserted abutting the plunger rod of thesyringe at the top of the barrel of the syringe (the proximal end of thesyringe) in between the grip-end of the plunger, and the excessformulation expelled until the spacer impedes further axial distalmotion of the plunger. This physical mechanism relieves the user fromhaving to visually determine or “eye-ball” the correct dose volumeloaded in the syringe. The dose loading spacer guide can then be removedfrom the syringe device. Because many syringes comprise elastomericgaskets as seals at the proximal end of the syringe barrel such thatindividual user strength in depressing the plunger can lead to variationin the a dose delivered, a dose dispensing guide can be placed on theplunger (or has already been placed on the syringe plunger “as sold”),which guide is configured generally as a “ring” that physically impedesfurther depression of the plunger after the correct dose volume has beendelivered into the eye. Syringe loading and dosing guides have been madecommercially (Berlin Food & Lab Equip., South San Francisco, Calif.;Encore Machining, San Jose, Calif.), and specifications are designed forthe particular syringe and dose volume. For example, using such dosingand delivery guides, minute amounts of medicament, such as about 5.0 μLor about 7.5 μL, can be placed into the eye, depending on the sizeguide(s) used. Syringes suitable for use in delivering the formulationsinclude disposable insulin syringes with permanently attached needles,particularly a 0.3 mL sterile insulin syringe (Becton Dickenson), or asterile single-use glass syringe without attached needle, such as a 0.5ml glass syringe (Hypak by Becton Dickenson). In one embodiment, theformulation, syringe, cannula or needle, dose loading guide and,optionally, dose delivery guide are included in a kit for accurateadministration of the formulation dose unit.

The administration of a single dose of the formulation consistingessentially of dexamethasone in citrate has been observed to adequatelycontrol (prevent or ameliorate) inflammation following cataract surgeryin humans. Thus, a particular embodiment of the present inventionprovides for the use of a dosage form of about 5 μL of a formulationconsisting essentially of dexamethasone and ATEC in a singleadministration into the anterior chamber for the treatment ofinflammation in the human eye following cataract surgery. Thedexamethasone can be present in the particular embodiment is in theconcentration of example, about 6%, about 9% or about 12% (w/w). Asexamples, the dexamethasone can be in an amount of about 342 μg, about517 μg, or about 697 μg in the dosage form volume of about 5 μLdelivered into the anterior chamber of the eye. More specifically, for alow dose formulation consisting of 6% dexamethasone, a 5 μL dose weighs5.7 mg, and contains 0.342 mg dexamethasone and 5.358 mg ATEC; for amedium dose of 9% dexamethasone, a 5 μL dose weighs 5.75 mg, andcontains 0.5175 mg dexamethasone and 5.2325 mg ATEC. These dosage formsare injected only once: at the time of cataract surgery, after thesurgery is complete and while the patient is still under anesthesia(local or systemic anesthesia). The administration is done after the newlens has been inserted, essentially after the cataract replacementportion of the surgery has been completed.

The present use can be combined with other therapies. Antibiotic therapywill likely be used after cataract surgery, such as antibiotic drops orsustained release antibiotic therapy (see U.S. Pat. No. 7,906,136), asthe healthcare provider prescribes. Additionally, should the patientrequire additional anti-inflammatory medications for some reason, theseare not contraindicated by the use of the present formulations. Also,some patients may need anti-glaucoma therapy after cataract surgery.These therapies are known in the art.

Another aspect of the present invention provides for use of aformulation consisting of dexamethasone in ATEC for the preparation of amedicament for the treatment of intraocular inflammation followingcataract surgery wherein the single, fixed dosage amount is, forexample, about 5 μL of about 342 μg, 517 μg, or 697 μg of dexamethasone.

Importantly, the present invention provides use of a formulation thattreats an acute inflammatory response to a surgical event. By design itis formulated to deliver an immediate, high dose very quickly to give aquick response. The amount of dexamethasone released from theformulation then tapers off quickly to minimize the potential of anyadverse events associated with the use of steroids. In clinical trials,this use resulted in positive outcome for humans following cataractsurgery.

EXAMPLES Example 1. In Vitro Release of Dexamethasone from CitrateFormulations

A series of in vitro experiments were conducted to measure thedexamethasone release kinetics from formulations of dexamethasone andcitrate. Liquid formulations of dexamethasone (Dex) and triethylO-acetyl citrate (ATEC) were made by weighing each component and mixingthem together with ample stirring to form a homogenous mixture (drugproduct). A volume of 5 μL of the following three separate formulationsof Dex/ATEC drug product was used in the in vitro study:

342 μg/5 μL, Equivalent dose: 342 μg

517 μg/5 μL, Equivalent dose: 517 μg

697 μg/5 μL, Equivalent dose: 697 μg

Five microliters (5 μL) of the drug product was placed in a 20 mLscintillation vial then a sufficient quantity (q.s.) of saline solution(0.9% NaCl, pH 6-8) added to bring the total volume to 10 mL. The vialscontaining the drug product in saline were incubated at 37° C. At eachtime point, the sample vials were removed from the incubator and cooledto room temperature. Aliquots of solution (5 mL) were removed from eachvial and tested for dexamethasone concentration using ultra performanceliquid chromatography. Five mL of fresh saline was added back to eachtest vial to maintain infinite sink conditions, and the sample vialsplaced back into the incubator at 37° C. Aliquots were removed, as justdescribed, and tested on days 1, 3, 7 and weekly thereafter fordexamethasone release. This drug release measurement approach isreferred to as the 5/10 saline drug release method, because the totalvolume was 10 ml and the amount removed and replaced for testing was 5mL. The in vitro Dex average release from the drug product is shown inTable 1 (see also FIG. 1):

TABLE 1 Dexamethasone Average Percent Release in 10 mL Saline Time(Days) Ave. % Total Dex Released SD % RSD Drug Product 342 μg Dex 1 44.61.8 4.0 3 71.1 3.0 4.2 7 97.3 2.8 2.9 Drug Product 517 μg Dex 1 30.5 0.92.8 3 48.3 1.6 3.3 7 70.6 4.1 5.9 14 87.0 2.6 3.0 21 98.7 2.2 2.2 DrugProduct 697 μg Dex 1 23.5 1.7 7.1 3 40.9 3.3 8.1 7 59.5 3.3 5.5 14 76.92.8 3.7 21 90.9 4.1 4.5 28 96.1 4.5 4.7 35 99.8 1.2 1.3 n = 6 for eachtime point.

In another in vitro test series, 342 μg/5 μL or 517 μg/5 μL (Dex inATEC) were placed in vials and q.s. to 20 mL with 0.9% saline. Storageand testing were conducted as above, except that at each time point 15mL withdrawn for sampling and was replaced with 15 mL of fresh saline.This method was named the 15/20 saline drug release method. The releaseof Dex from the drug product is shown in Table 2 (see also FIG. 2):

TABLE 2 Dexamethasone Average Percent Release in 20 mL Saline Time(Days) Ave. % Total Dex Released SD % RSD Drug Product 342 μg Dex 143.49 0.42 0.97 3 66.20 0.37 0.56 7 87.73 0.72 0.82 14 97.36 0.74 0.76Drug Product 517 μg Dex 1 30.70 0.58 1.88 3 53.01 1.25 2.36 7 76.66 1.862.42 14 99.14 0.59 0.59 n = 6 for each time point.

To test in vitro release in an alternative buffer system, 342 μg/5 μL or517 μg/5 μL (Dex in ATEC) were placed in vials and q.s. to 20 mL with asolution of 0.9% saline, 0.05% β-cyclodextrin. Storage and testing wereconducted as above, except that at each time point 10 mL withdrawn forsampling and was replaced with 10 mL of fresh solution. This method wasnamed the 10/20 saline/BCD drug release method. The release of Dex fromthe drug product is shown in Table 3 (see also FIG. 3):

TABLE 3 Dexamethasone Average Percent Release in 20 mLSaline/β-cyclodextrin Time (Days) Ave. % Total Dex Released SD % RSDDrug Product 342 μg Dex 1 54.40 2.35 4.33 3 87.04 7.67 8.81 7 99.23 0.950.96 Drug Product 517 μg Dex 1 39.34 1.02 2.60 3 70.11 7.14 10.19 797.39 4.79 4.92 n = 6 for each time point.

Another in vitro release in an alternative buffer system was undertaken,in which 342 μg/5 μL or 517 μg/5 μL (Dex in ATEC) were placed in vialsand q.s. to 20 mL with a solution of 0.9% saline, 0.05% Tween-80.Storage and testing were conducted as above, except that at each timepoint 10 mL withdrawn for sampling and was replaced with 10 mL of freshsolution. This method was named the 10/20 saline/T80 drug releasemethod. The release of Dex from the drug product is shown in Table 4(see also FIG. 4):

TABLE 4 Dexamethasone Average Percent Release in 20 mL Saline/Tween-80Time (Days) Ave. % Total Dex Released SD % RSD Drug Product 342 μg Dex 139.69 3.29 8.28 3 75.71 10.23 13.52 7 92.44 5.70 6.16 Drug Product 517μg Dex 1 29.06 4.08 14.05 3 59.77 11.86 19.84 7 90.14 10.00 11.10 n = 6for each time point.

Example 2. In Vivo Release of Dexamethasone from Citrate

Liquid formulations of dexamethasone and ATEC were made by weighing eachcomponent and mixing them together with ample stirring to form ahomogenous mixture, a uniformed blend. Dexamethasone, USP micronized,GMP manufacturing, is commercially available (e.g., IIawkinsPharmaceutical Group, Minneapolis, Minn.; Pharmacia Upjohn, Kalamazoo,Mich.), with a certificate of analysis. Additional tests for identityand purity of dexamethasone were undertaken using infrared absorptionand HPLC. ATEC, NF, is available commercially (e.g., from VertellusPerformance Materials Inc., Greensboro, N.C.) with a certificate ofanalysis. Additional testing for identity and purity were undertaken.The formulations were either 6%, 9% or 12% dexamethasone, such that each5 μL dose contained 342 μg, 517 μg or 697 μg dexamethasone. Using a 30gauge needle, a single dose of 5 μL was injected under humane conditionsinto the anterior chamber of the eyes of rabbits. Subsequently, samplesof the aqueous humor of treated eyes were collected (generally about 100μL to 150 μL, in volume), pooled, concentrated 10-fold, and analyzed byliquid chromatography-mass spectrometry (LCMS) to afford the level ofdexamethasone released into the aqueous humour. This drug release studywas named the in vivo aqueous humor Dex release study. The sampling daysand results are shown in FIG. 6. Dexamethasone was released for about 11to about 21 days. One skilled in the art can readily extrapolate thesustained release profile from FIG. 6.

Example 3. Use of Sustained Release Dexamethasone Post Cataract Surgery

A Phase II post-cataract surgery inflammation study was undertaken tocompare three dosage forms of short-term sustained releasedexamethasone. This was a multicenter, randomized, double-masked, doseranging study for efficacy and safety. The human patients were over 40years of age, having visual acuity potential greater than 20/30 in thestudy eye and having a corneal endothelial cell count of ≥2000 cells/mm²underwent unilateral cataract surgery by phacoemulsification. Patientseye were excluded from the study who had (a) used any ocular, topical ororal corticosteroids within 7 days prior to day 0; (b) received aperiocular corticosteroid injection in the study eye in the 3 monthsprior to screening; (c) used topical NSAIDs in the study eye within 15days prior to screening; or (d) received any intravitreal corticosteroiddelivery vehicle (e.g., Restisert or Ozurdex), in the study eye.

Dexamethasone in ATEC, prepared as a mixture as in Example 2, wassupplied with a fill volume of 0.5 mL and packaged in a 2 mL glass vial,sealed with a ruber stopper and an aluminum seal. Each vial was intendedto be used only once. The formulations were sterile, preservative-freesuspensions; sterilization was accomplished using E-beam at 28±3 kGyafter vial fill. Particle size % volume-size was 10%<10.0 μm, 50%<30.0μm, 90%<90 μm. SOP for product content, uniformity, endotoxin, pH,sterility, etc. were followed. Dexamethasone release in saline from the697 μg/5 μL, Dex, average value n=6: 24 hours: 10%-50% (ave. 20.4%), 3days: 30%-70% (ave. 41.0%), 7 days: 45%-90% (ave. 57.4%). Dexamethasonerelease in saline from the 517 μg/5 μL, Dex, average value n=6: 24hours: 15%-55% (ave. 27.6%), 3 days: 35%-75% (ave. 47.1%), 7 days:50%-95% (ave. 66.8%). Dexamethasone release in saline from the 342 μg/5μL, Dex, average value n=6: 24 hours: 15%-55% (ave. 39.2%), 3 days:40%-80% (ave. 62.4%), 7 days: >50% (ave. 89.1%).

Osmolality was tested by incubating a 5 μL aliquot in 4.5 mL or 0.45%saline at 37° C. overnight, then samples were allowed to cool to roomtemperature and osmolality compared with 0.45% saline. The data observedwas: 0.45% saline, pH 6.55, mOsm (milli Osmols per liter) 147; 342 μg/5μL Dex, pH 6.56, mOsm 148; 517 μg/5 μL Dex, pH 6.50 mOsm 150; 697 μg/5μL Dex, pII6.40, mOsm 174.

Viscosity was also measured at 25° C. At shear rates ranging from 7.5 to23.55 sec−1, the viscosity of 697 μg/5 μL Dex ranged from 106.66 cp to84.24 cp. At shear rates ranging from 7.50 to 34.28 sec−1, the viscosityof 517 μg/5 μL Dex ranged from 73.87 cP to 62.64 cP. At shear ratesranging from 7.50 to 45.00 sec−1, the viscosity of 342 μg/5 μL Dexranged from 53.02 cP to 43.47 cP. From the viscosity data, theformulations showed characteristics of Non-Newtonian (pseudo-plastic)fluids. See also FIG. 5.

After the completion of cataract surgery, a single dose containingeither 342 μg, 517 μg or 697 μg Dex in ATEC was delivered by injectionusing a disposable sterile insulin syringe that was used to withdraw andinject about 5 μL, using syringe loading and dosing guides to positionthe plunger to deliver a unit dose volume of 5 μL into the anteriorchamber of the study eye. The amount of dexamethasone per patient wasassigned at random. Anterior chamber cells (ACC) were graded as a scoreof 0 to 4, assessed by slit lamp biomicroscopy. Ocular and non-ocularsafety was monitored through day 90.

As a primary endpoint, the proportion of patients with ACC Grade=0 atday 8 was 53.4%/342 μg (n=58), 51.8%/517 μg (n=56), and 63.8%/697 μg(n=58). See FIG. 7. As a secondary endpoint, the proportion of patientwith ACC Grade=0 over time is shown in FIG. 8. There was nostatistically significant difference among the three treatment groups.

Regarding safety and efficacy, no patients suffered suprachoroidalhemorrhage or retinal detachment, and only on patient (in the 342 μggroup) suffered endophthalmitis. The study eye serious adverse eventswere consistent with published serious adverse events following cataractsurgery.

Example 4. Comparative Efficacy

Use of three formulations of dexamethasone in citrate (as described inExamples 2 and 3) was compared with standard anti-inflammatory eye dropstherapy in reduction of anterior chamber inflammation.

For a comparison with steroidal Lotemax® (loteprednol 0.5%), data wascollected in which the primary endpoint was reduction of anteriorchamber inflammation (ACI), the sum of anterior chamber cells (ACC=0-5cells* and flare=0) in the post-operative eye:

loteprednol QID Vehicle Trial 1 - Visit Days 7-12** 43% 18% Trial 2 -Visit Days 7-12** 34% 17% *For ACC grading, this endpoint is equivalentto ACC Grade 0 and 1 for IBI-10090. **The Target Date was Day 8, butallowed patients to receive the dose up to Day 12.

For comparison with steroidal Durazol® (difluprednate 0.05%), data wascollected in which the primary endpoint was the proportion of subjectswith an anterior chamber cell grade of “0” on Day 8:

difluprednate QID Vehicle Trial 1 Day 3  7.3%   0% Day 8 23.6% 10.3% Day 15 45.0%  14% Trial 2 Day 3  1.9% 1.7% Day 8 21.2% 5.3% Day 15 36.5%8.8%

For comparison with an NSAID eye drop, Acuvail® (ketorolac 0.4%) theprimary endpoint was the proportion of patients with clearing ofanterior chamber inflammation (summed ocular inflammation score=0):

ketorolac BID Vehicle Trial 1 Day 8 29% 16% Day 14 46% 25% Trial 2 Day 833% 17% Day 14 58% 25%

For comparison with another NSAID eye drop, Bromday® (bromfenac 0.09%),the primary endpoint was the sum of anterior chamber cell (ACC=0-5cells)* and flare equal to zero at Day 15:

bromfenac 0.09% Vehicle Trial 1 Day 8 33.8% 13.3% Day 14 62.6% 39.8%Trial 2 Day 8 38.6% 21.9% Day 14 65.8% 47.9% *For ACC grading, thisendpoint is equivalent to ACC Grade 0 and 1 for the injecteddexamethasone in citrate. These numbers also included patients who wereon additional anti-inflammatory drops.

For comparison with another brofenac NSAID eye drop, Prolensa®(bromfenac 0.07%), the primary endpoint was the proportion of patientswith clearance of ocular inflammation (0 cell and no flare):

bromfenac 0.07% Vehicle Trial 1 Day 8 24.1%  6.5% Day 14 45.5% 13.0%Trial 2 Day 8 30.0% 12.7% Day 14 45.5% 27.3% Dosing schedule: Day beforesurgery, prior to surgery, once a day thereafter.

For comparison with another NSAID eye drop, Ilevro® (nepafenac 0.3%),the primary endpoint was the proportion of patients with clearance ofocular inflammation (0 cell and no flare) at Day 7:

nepafenac 0.3% Vehicle Trial 1 Day 3 11.4% 10.7% Day 7 34.1% 18.8% Day14 68.4% 34.0% Trial 2 Day 3  6.4%  3.2% Day 7 31.3% 10.3% Day 14 64.6%25.0% Dosing schedule: Day before surgery, prior to surgery, once a daythereafter.

An additional comparison was undertaken measuring anterior chamber cellclearing in human patients. A comparison graph is shown in FIG. 9, foranterior chamber cell clearing at Day 8 and Day 15, created usingpreliminary data in twenty-six patients treated with dexamethasone incitrate following cataract surgery as described herein, compared withpublished data for anterior chamber cell clearing using Durezol®difluprednate steroid eye drops and Surodex® PLGA-based sustainedrelease-dexamethasone implant.

When data for commercially available drug products are compared withdata for the injected formulations as described herein, it is clear thatthe efficacy provided by the instant embodiments is superior to otherdosage forms and regimens.

We claim:
 1. A kit for the treatment of inflammation in the eyecomprising: a vial containing a formulation consisting essentially ofdexamethasone and triethyl acetyl citrate, wherein the w/w ratio of thedexamethasone:triethyl acetyl citrate is selected from the groupconsisting of about 6:94, about 9:91, and about 12:88; an injectionsyringe; a needle; a cannula; a dose loading guide; and a dose deliveryguide.
 2. The kit of claim 1, wherein the dose loading guide is designedto load a dose of about 4 μL to about 6 μL.
 3. The kit of claim 2,wherein the dose loading guide is designed to load a dose of about 5 uL.4. The kit of claim 1, wherein the concentration of the dexamethasone isabout 9% w/w and the concentration of the triethyl acetyl citrate isabout 91% w/w.
 5. The kit of claim 4, wherein the dose loading guide isdesigned to load a dose of about 5 uL.
 6. The kit of claim 1, furthercomprising instructions for administration of a single unit dose ofabout 5 μL of the formulation into the anterior chamber of the eyefollowing cataract surgery.
 7. A unit dosage form consisting essentiallyof about 4 μL to about 6 μL of a composition consisting essentially ofabout 9% (w/w) dexamethasone and about 91% (w/w) triethyl acetylcitrate.
 8. The unit dosage form of claim 7, wherein the volume of thecomposition is about 5 μL.
 9. The unit dosage form of claim 7, whereinthe dose of the dexamethasone in the pharmaceutical composition is about342 μg to about 697 μg.
 10. The unit dosage form of claim 7, wherein thedose of dexamethasone in the composition is about 517 μg.
 11. A unitdosage form comprising an injection syringe containing about 4 μL toabout 6 μL of a composition consisting essentially of about 9% (w/w)dexamethasone and about 91% (w/w) triethyl acetyl citrate.
 12. The unitdosage form of claim 11, wherein the volume of the composition is about5 μL.
 13. The unit dosage form of claim 11, wherein the dose of thedexamethasone in the pharmaceutical composition is about 342 μg to about697 μg.
 14. The unit dosage form of claim 11, wherein the dose ofdexamethasone in the composition is about 517 μg.